反应详情

温度

100 °C

To a solution of 6-chloro-1-(2,2,2-trifluoro-ethyl)-1H-quinazoline-2,4-dione (1.10 g, 3.97 mmol) in phosphorous oxychloride (15 mL) was added 1 mL triethylamine. The reaction was heated to 100° C., stirred for 4 hrs and concentrated. The crude residue was dissolved in chloroform, washed with 1 N aq sodium hydroxide, dried over Na2SO4, filtered, and concentrated. To a solution of the crude residue in DMF (50 mL), was added triethylamine (1 mL) and 3-amino-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.0 g, 5.50 mmol). The solution was heated to 50° C. and stirred for 12 hrs. The reaction was partitioned between ethyl acetate and water and the organic phase was washed an additional 2× with water and brine, dried over Na2SO4, filtered, and concentrated. The resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C. After 4 hrs the solution was cooled and concentrated (1.1 g). 1H NMR (300 MHz, CD3OD) δ ppm 2.20 (m, 8H), 4.16 (m, 2H), 4.65 (m, 1H), 5.04 (q, J=8.6 Hz, 2H), 7.62 (d, J=9.0 Hz, 1H), 7.83 (dd, J=2.2, 9.0 Hz, 1H), 8.47 (d, J=2.2 Hz, 1H); MS (ESI+Q1MS) m/z 388 [M+2H]+

1. concentrationconcentrated
2. dissolutionThe crude residue was dissolved in chloroform
3. washwashed with 1 N aq sodium hydroxide
4. dry with materialdried over Na2SO4
5. filtrationfiltered
6. concentrationconcentrated
7. temperatureThe solution was heated to 50° C.
8. stirringstirred for 12 hrs
9. customThe reaction was partitioned between ethyl acetate and water
10. washthe organic phase was washed an additional 2× with water and brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationconcentrated
14. additionThe resultant yellow foam was treated with HBr solution (6 mL, 30 weight % in AcOH) in a pressure vessel at 100° C
15. temperatureAfter 4 hrs the solution was cooled
16. concentrationconcentrated (1.1 g)